title: The BRICHOS domain, amyloid fibril formation, and their relationship.
abstract: Amyloid diseases are defined by tissue deposition of insoluble, fibrillar β-sheet polymers of specific proteins, but it appears that toxic oligomeric species rather than the fibrils are the main cause of tissue degeneration. Many proteins can form amyloid-like fibrils in vitro, but only ~30 proteins have been found to cause mammalian amyloid disease, suggesting that physiological mechanisms that protect against amyloid formation exist. The transmembrane region of lung surfactant protein C precursor (proSP-C) forms amyloid-like fibrils in vitro, and SP-C amyloid has been found in lung tissue from patients with interstitial lung disease (ILD). ProSP-C contains a BRICHOS domain, in which many ILD-associated mutations are localized, and the BRICHOS domain can prevent SP-C from forming amyloid-like fibrils. Recent data suggest that recombinant BRICHOS domains from proSP-C and Bri2 (associated with familial dementia and amyloid formation) interact with peptides with a strong propensity to form β-sheet structures, including amyloid β-peptide associated with Alzheimer's disease. Such interactions efficiently delay formation of fibrils and oligomers. The BRICHOS domain is defined at the sequence level and is found in ~10 distantly related proprotein families. These have widely different or unknown functions, but several of the proteins are associated with human disease. Structural modeling of various BRICHOS domains, based on the X-ray structure of the proSP-C BRICHOS domain, identifies a conserved region that is structurally complementary to the β-sheet- and/or amyloid-prone regions in the BRICHOS domain-containing proproteins. These observations make the BRICHOS domain the first example of a chaperone-like domain with specificity for β-prone regions.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University , 751 05 Uppsala, Sweden.
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Knight
authors.forename: Jenny
authors.initials: J
authors.lastname: Presto
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D017124:Conserved Sequence; D003704:Dementia / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D054730:Protein Interaction Domains and Motifs; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D017386:Sequence Homology, Amino Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D018697:Nootropic Agents; D010446:Peptide Fragments; D011498:Protein Precursors; D037721:Pulmonary Surfactant-Associated Protein C; D011994:Recombinant Proteins; C489679:SFTPC protein, human